It is to be noted that throughout this application various publications are referenced by Arabic numerals within brackets. Full citations for these publications are listed at the end of the specification. The disclosures of these publications are hereby incorporated by reference in their entireties in order to more fully describe the state of the art to which this invention pertains.
Coronary heart-disease (CHD) is a leading cause of troublesome quality of life, and mortality among the populations of the developed nations and the economically fast-growing countries with worldwide reise in obesity, diabetes, including among young adults, due to high-calories diets and poor exercise time. The cardiovascular disease is characterized by clogged arteries and reduced supply of blood and nutrients to the heart muscle caused by lipid deposition inside the arterial wall. Hyperlipidemia or hyperlipoproteinemia (form lipid-protein complexes) may be caused by genetic factors or by obesity and metabolic disorders. Lipid-protein complexes are spherical aggregates consisting of a hydrophobic core composed of lipids (triglycerides and cholesterol esters) surrounded by hydrophilic exterior shell of about 2 nm composed of apoproteins, cholesterol, and phospholipids. The hydrophilic polar surface keeps the lipids dissolved and circulating in the plasma. Based on the size and density, four main lipoproteins prevalent in the plasma: chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL or LDL-C), and high density lipoprotein (HDL oar HDL-C). Chylomicrons and VLDL are rich in triglycerides and cholesterol. The are the sources of fatty acids in muscles and adipose tissues. LDL-C particles are rich in cholesterol and are produced in the liver from dietary cholesterol, from liver-synthesized cholesterol, and from remnants of chylomicrons and VLDL that have entered the extrahepatic tissues from the general circulation [1].
High levels of LDL-C (referred to as ‘bad cholesterol’) is a well established major risk factor in CHD, but is effectively treated with HMG-CoA reductase inhibitors (statins) leading to substantial reduction in cardiovascular morbidity and mortality [2]. HDL-C particles (referred to as ‘good cholesterol’) are responsible for a cleansing mechanism called ‘reverse cholesterol transport,’ where the cholesterol is transported from extrahepatic tissues to the liver for catabolic destruction and excretion. It is widely accepted that low levels of HDL-C and high levels of triglycerides in plasma are important risk factors contributing to CHD [3].
Levocarnitine (L-carnitine or vitamin BT) belongs to a class of water soluble vitamins which includes vitamin B-12,folic acid, biotin, vitamin B-6,and mevalonic acid. It occurs naturally, and serves as a cofactor in fatty acid metabolism for energy production. This cofactor functions by birding activated fatty acids in the form of acyl carnitine (carnitine shuttle). Use of 1-carnitine in the treatment of hyperlipoproteinemia, hyperlipidemia, and myocardial dysfunction has been the subject of intensive investigation [4-9]. L-carnitine has also been reported to be useful as an adjuvant therapy in the management of renal anemia [10]. Propionyl carnitine (the propionic ester of carnitine) has been shown to improve cardiac function [11, 12]. Acetyl carnitine has been proposed as a possible therapeutic agent for Alzheimer's disease [13]. Recently, CPS 124,a carnitine monothiophosphate derivative which is a reversible and competitive inhibitor of carnitine palmitoyl transferase I, is reportedly undergoing clinical development for the treatment of non-insulin dependent diabetes mellitus (NIDDM) [14].
In humans, fibrates such as clofibrate, bezafibrate, fenofibrate, etofibrate, gernfibrozil, G10-2331,which are agonists of PPAR-alpha have been successfully used to treat hypertriglyceridemia. They function by increasing the clearance and decreasing the synthesis of VLDL. The fibtrates, however, have only a modest effect (10-20%) in increasing HDL-C levels [15, 16]. Clinical development of cardioprotective HDL-C elevating agents is a major current therapeutic goal. Recently, it was shown that oxa substituted α,ω-alkanedicarboxylic acids and related compounds raise serum HDL-levels significantly [17]. In particular, CI-1027 has been in clinical trials. Also, long chain α,ω-alkanedicarboxylic acids are also in clinical development as hypolipidemic agents [18,19].
In view of the extensive work in the treatment of hyperlipoproteinemia, hyperlipidemia, and myocardial dysfunction with L-camnitine, L-propionyl carnitine, CI-1027 and its analogs, and fibric acids, it is surprising that covalent conjugates of any two or more of these drugs have not been proposed. Therefore, the present invention introduces a novel concept referred to as ‘double prodrug’ approach which involves the preparation of novel covalent conjugates comprising two or more drugs, and their use in the treatment of various cardiovascular disorders. A suitable covalent attachment of two more of these cardiovascular agents will have a significant therapeutic value in that a single molecular entity may have multiple therapeutic effects resulting from diverse, but synergistic mechanism of action, and controlled release of both drugs in vivo through enzymatic hydrolysis of the conjugate. The concept of the present invention is not limited to cardiovascular applications; other therapeutic applications, including CNS disorders, diabetes, cancer, inflammation, and the like are also contemplated.